Cannabidiol for Bilateral Total Knee Arthroplasty

Effects of Cannabidiol (CBD) Oral Solution in Patients Undergoing Bilateral Total Knee Arthroplasty: a Randomized, Controlled, Parallel, Triple Blind, Pilot Study

In light of the opioid epidemic and evidence suggesting that cannabis may be opioid-sparing, we are in a unique position to conduct a novel, high-impact study that would set the stage for future RCTs examining the effects of a nonintoxicating and nonaddictive cannabinoid in an orthopedic patient population. Epidiolex®, an oral cannabidiol (CBD) solution, is the first ever cannabis-derived medication to be approved by the Food & Drug Administration. Our aim is to conduct a pilot study using a placebo oral solution, 400mg and 800mg Epidiolex® to gather data on its effects on patients undergoing bilateral total knee arthroplasty (BTKA). We will be estimating whether Epidiolex® is associated with minimal opioid use and adequate analgesia. We will also assess its tolerability, pharmacokinetics, and effects on inflammatory markers in the perioperative setting.

Study Overview

• Status: Recruiting
• Conditions: Pain, Postoperative; Knee Osteoarthritis; Opioid Use
• Intervention / Treatment: Other: Ora-sweet SF; Drug: cannabidiol

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: William Chan, MEng; Phone Number: 917-260-4788; Email: chanw@hss.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10021
      • Recruiting
      • Hospital for Special Surgery
      • Contact: William Chan, MEng; Phone Number: 917-260-4788; Email: chanw@hss.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18 to 75
• Scheduled for same-day bilateral total knee replacements with participating surgeons
• American Society of Anesthesiologists (ASA) Physical Status 1 or 2

Exclusion Criteria:

• ASA 3 and higher
• Weight < 40kg
• Planned use of general anesthesia
• Contraindication to major components of study protocol
• Cannabis or cannabinoid use within the past 3 months (recreational and/or medical)
• Use or ingestion of hemp seeds or hemp oil in any form within the past 30 days
• Chronic opioid use (>3 months)
• Coumadin use
• Current use of SSRI or SNRIs
• History of substance abuse or dependence
• Active or history of major psychiatric illness
• Severe cardiovascular disorder
• Severe hepatic or renal insufficiency (transaminase levels above ULN)
• History of epilepsy
• Diagnosis of rheumatic disease, autoimmune disease, or immunodeficiency (e.g. rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, multiple sclerosis, etc.)
• Use of valproate or clobazam
• Known or suspected hypersensitivity, allergy, or contraindication to cannabinoids or any of the excipients in the study medications (i.e. sesame oil, sucralose, strawberry flavor)
• Active use of steroids - oral steroids upon admission
• Stress dose steroids
• Non-English speakers
• Planned discharge to home without caregiver(s)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Ora-sweet SF	Other: Ora-sweet SF; Ora-sweet SF placebo
Experimental: 400mg cannabidiol	Drug: cannabidiol; Epidiolex (cannabidiol) oral solution; Other Names: Epidiolex
Experimental: 800mg cannabidiol	Drug: cannabidiol; Epidiolex (cannabidiol) oral solution; Other Names: Epidiolex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Opioid Usage in First 72 hours Postoperatively	Cumulative opioid usage over the first 72 hours after surgery. Measured in morphine equivalents (ME), a scale that measure opioid usage among all opioid medications	0-72 hours postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of CBD	Levels of CBD in the blood. This is measured using blood draws and lab analysis.	0, 1, 2, 3, 4, 6 hours after medication administration
Levels of Plasma Inflammatory Marker Interleukin-6	Interleukin-6 (IL6) is an inflammatory marker found in plasma. The levels of IL6 are measured using blood draws and lab analysis.	Preoperative, Postoperative day 1
NRS Pain at rest	Pain at rest measured using numerical rating scale(NRS) from 0-10, with 0 being no pain at all to 10 being the worst pain imaginable.	Preoperatively; postoperatively in the PACU, morning of postoperative day (POD) 1,2,3,4,7 and at 3 months
NRS Pain with movement	Pain with movement using numerical rating scale(NRS) from 0-10, with 0 being no pain at all to 10 being the worst pain imaginable.	Preoperatively; morning of postoperative day (POD) 1,2,3,4,7 and at 3 months
Brief Pain Inventory Short Form	Brief Pain inventory short form measures the severity of pain and its impact on function. It measures pain from 0-10 0 being no pain whatsoever to 10 being the worst pain imaginable. It measures impact on function from 0-10, 0 being no impact whatsoever to 10 being completely impactful.	Preoperatively; morning of postoperative day (POD) 1,2,3,4,7 and at 3 months
Incidence of adverse events	Adverse events, including allergic reactions, pyrexia (fever), somnolence (excessive sleepiness), GI problems (upset stomach, diarrhea), dry mouth, escalation of post-operative opioid requirement	Postoperatively in the PACU; morning of postoperative day (POD) 1,2,3,4,7 and at 3 months
Opioid related Symptom Distress Scale (ORSDS)	ORSDS measures opioid related side effects. There are 13 side effects with 3 subcategories (severity, frequency, bothersomeness) each with 5 different responses (scored 0-4).	Morning of postoperative day (POD) 1,2,3,4,7 and at 3 months
Anxiety levels	Hospital Anxiety and Depression Scale (HADS) asks 14 questions, 7 about anxiety and 7 about depression. Responses are scored from 0-3. Responses between the two categories are summed and scoring is as follows: 0-7 = normal, 8-10=borderlines abnormal, 11-21=abnormal	Preoperatively; Morning of postoperative day (POD) 1,2,3,4,7 and at 3 months
Cumulative inpatient analgesic use (non-opioid)	Total non-opioid medication usage	POD0 - POD3
Opioid & non-opioid analgesic consumption	Total opioid & non-opioid medication usage	At hospital discharge to POD7 and at 3 months
Hospital length of stay	Length of stay measured in hours	End of surgery to hospital discharge
Blinding Assessment	Patients are asked which treatment they think they received. The correctness of their guesses is then measured using the bang-blinding index to see if patients were able to accurately guess which treatment they received. It is measured on a scale of -1 to 1. Scores closer to 0 indicate better blinding, or patients not being able to guess their treatment	POD4
Time to reach discharge physical therapy goals	Physical therapy goals for total knee replacement include walking 100 feet, going up and down 4 stairs, and independent transfer (meaning they can move from a lying to standing position independently). Patients need to complete these goals before being discharged	At hospital discharge - up to 3 days after surgery
Range of motion	Range of motion, or extension and flexion of the knees, are measured preoperatively and at the patients' 6 week surgeon visit. It is measured in degrees	preoperatively, 6 weeks postoperatively.
Sleep quality and duration	Sleep quality assessed by actigraphy using ActiGraph wGT3X-BT activity monitor	POD0 - POD3
Sleep quality	Sleep quality assessed by Leeds sleep evaluation questionnaire (LSEQ). Responses to 10 questions will be measured on a slider scale ranging from 0-100.	preoperatively; morning of postoperative day (POD) 1,2,3,4,7 and at 3 months

Collaborators and Investigators

• Sponsor: Hospital for Special Surgery, New York
• Investigators: Principal Investigator: Alexandra Sideris, PhD, Hospital for Special Surgery, New York

Study record dates

Study Major Dates

• Study Start (Actual): November 2, 2022
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): October 1, 2024

Study Registration Dates

• First Submitted: February 5, 2021
• First Submitted That Met QC Criteria: February 8, 2021
• First Posted (Actual): February 11, 2021

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Anticonvulsants; Cannabidiol
• Other Study ID Numbers: 2019-1688

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) will be shared.
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication
• IPD Sharing Access Criteria: For researchers who provide a methodologically sound proposal and analyses to achieve aims in the approved proposal. Proposals should be directed to siderisa@hss.edu. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes